Menu
GeneBe

rs771578775

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020247.5(COQ8A):c.1042C>T(p.Arg348Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,598,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 2.58
Variant links:
Genes affected
COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-226982996-C-T is Pathogenic according to our data. Variant chr1-226982996-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 242458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226982996-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COQ8ANM_020247.5 linkuse as main transcriptc.1042C>T p.Arg348Ter stop_gained 8/15 ENST00000366777.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COQ8AENST00000366777.4 linkuse as main transcriptc.1042C>T p.Arg348Ter stop_gained 8/151 NM_020247.5 P1Q8NI60-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152220
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000453
AC:
10
AN:
220860
Hom.:
0
AF XY:
0.0000415
AC XY:
5
AN XY:
120374
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000943
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000718
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000353
AC:
51
AN:
1446646
Hom.:
0
Cov.:
34
AF XY:
0.0000390
AC XY:
28
AN XY:
718652
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000937
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000259
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000398
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152220
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000844
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 13, 2021Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24218524, 21873089, 20580948, 25525159, 28125198, 29915382, 31589614, 32337771) -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 22, 2023This sequence change creates a premature translational stop signal (p.Arg348*) in the COQ8A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COQ8A are known to be pathogenic (PMID: 18319074, 20580948). This variant is present in population databases (rs771578775, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with cerebellar ataxia and childhood onset ataxia (PMID: 20580948, 21873089, 29915382). ClinVar contains an entry for this variant (Variation ID: 242458). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2022COQ8A: PVS1, PM2, PM3 -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 31, 2023PP1, PM2, PS4_moderate, PVS1 -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:3Other:1
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 05, 2021- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.53
Cadd
Pathogenic
41
Dann
Uncertain
1.0
Eigen
Pathogenic
0.78
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.84
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;D
Vest4
0.90
GERP RS
5.7
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771578775; hg19: chr1-227170697; COSMIC: COSV64657577; COSMIC: COSV64657577; API